title: Identification of cardiac troponin I sequence motifs leading to heart failure by induction of myocardial inflammation and fibrosis.
abstract: BACKGROUND
  Despite the widespread use of cardiac troponins for diagnosis of myocyte injury and risk stratification in acute cardiac disorders, little is known about the long-term effects of the released troponins on cardiac function. Recently, we showed that an autoimmune response to cardiac troponin I (cTnI) induces severe inflammation and subsequent fibrosis in the myocardium. This autoimmune disorder predisposes to heart failure and cardiac death in mice.
  
  
  RESULTS
  To investigate the role of cTnI-specific T cells, T cells were isolated from splenocytes of mice immunized with murine cTnI (mcTnI). Wild-type mice that received mcTnI-specific T cells showed high mcTnI-specific antibody titers, increased production of the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha, severe inflammation and fibrosis in the myocardium, and reduced fractional shortening. To identify the antigenic determinants of troponin I responsible for the observed inflammation, fibrosis, and heart failure, 16 overlapping 16mer to 18mer peptides covering the entire amino acid sequence of mcTnI (211 residues) were synthesized. Only mice immunized with residues 105 to 122 of mcTnI developed significant inflammation and fibrosis in the myocardium, with increased expression of the inflammatory chemokines RANTES, monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, macrophage inflammatory protein-2, T-cell activation-3, and eotaxin and the chemokine receptors CCR1, CCR2, and CCR5. Mice immunized with the corresponding human cTnI residues 104 to 121 and the mcTnI residues 131 to 148 developed milder disease.
  
  
  CONCLUSIONS
  Transfer of troponin I-specific T cells can induce inflammation and fibrosis in wild-type mice, which leads to deterioration of contractile function. Furthermore, 2 sequence motifs of cTnI that induce inflammation and fibrosis in the myocardium are characterized.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany. ziya.kaya@med.uni-heidelberg.de
authors.forename: Ziya
authors.initials: Z
authors.lastname: Kaya
authors.forename: Stefan
authors.initials: S
authors.lastname: Göser
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Buss
authors.forename: Florian
authors.initials: F
authors.lastname: Leuschner
authors.forename: Renate
authors.initials: R
authors.lastname: Ottl
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Stefan
authors.initials: S
authors.lastname: Zittrich
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pfitzer
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D015551:Autoimmunity; D001842:Bone and Bones / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D007114:Immunization; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008968:Molecular Conformation; D009205:Myocarditis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000276:immunology; D019707:Receptors, Chemokine / Q000378:metabolism; D020539:Sequence Analysis, Protein; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D019210:Troponin I / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
chemical_list: D018925:Chemokines; D010446:Peptide Fragments; D019707:Receptors, Chemokine; D019210:Troponin I